N-RAP expression during mouse heart development

N-RAP gene expression and N-RAP localization were studied during mouse heart development using semiquantitative reverse transcriptase-polymerase chain reaction and immunofluorescence. N-RAP mRNA was detected at embryonic day (E) 10.5, significantly increased from E10.5 to E16.5, and remained essentially constant from E16.5 until 21 days after birth. In E9.5-10.5 heart tissue, N-RAP protein was primarily associated with developing premyofibril structures containing alpha-actinin, as well as with the Z-lines and M-lines of more-mature myofibrils. In contrast, N-cadherin was concentrated in patches at the periphery of the cardiomyocytes. N-RAP labeling markedly increased between E10.5 and E16.5; almost all of the up-regulated N-RAP was associated with intercalated disk structures, and the proportion of mature sarcomeres containing N-RAP decreased. In adult hearts, specific N-RAP staining was only observed at the intercalated disks and was not found in the sarcomeres. The results are consistent with N-RAP functioning as a catalytic scaffolding molecule, with low levels of the scaffold being sufficient to repetitively catalyze key steps in myofibril assembly

Cerebellar Disease in the Dog and Cat: A Literature Review and Clinical Case Study (1996-1998)

The aim of this thesis is to detail the history, clinical findings, ancillary investigations and, in some cases, pathological findings in 25 cases of cerebellar disease in dogs and cats which were presented to Glasgow University Veterinary School and Hospital during the period October 1996 to June 1998. Clinical findings were usually characteristic, although the signs could range from mild tremor and ataxia to severe generalised ataxia causing frequent falling over and difficulty in locomotion. Diffuse cerebellar diseases were more common than focal in this study. Both dogs and cats are susceptible to cerebellar diseases, however, the aetiologies vary between these two species, hi the dog, inflammatory disease of unknown aetiology (or steroid- responsive tremor syndrome) was the most common cause of cerebellar disease, affecting ten out of fourteen cases. In contrast, cerebellar hypoplasia possibly caused by panleukopaenia virus was the most common cause of cerebellar signs in the cats, affecting four out of eleven cases, while only one dog was diagnosed with a developmental abnormaly. Inflammatory cerebellar disease in the cats was caused most commonly by feline infectious peritonitis virus, which was diagnosed in two cats. Feline spongiform encephalopathy occurred in two cats. Degenerative cerebellar disorder was diagnosed in three cases, with a definite diagnosis of abiotrophy in two cases and lysosomal storage disease in a cat. Trauma or angiopathy was suspected in two cases. Cerebellar neoplasia was relatively rare, and was diagnosed only in one dog. A thorough physical and neurological examination was important in localising the lesion and determining whether a multisystemic disease was present. However, in most cases, a definite diagnosis could not be achieved on the basis of history and clinical findings. CSF analysis was found to be useful in some cases, especially in ruling in an inflammatory cause. The definitive diagnosis was made by histopathological examination in six cases. The pathological findings are discussed in relation to the literature

Multimodality Data Integration in Epilepsy

An important goal of software development in the medical field is the design of methods which are able to integrate information obtained from various imaging and nonimaging modalities into a cohesive framework in order to understand the results of qualitatively different measurements in a larger context. Moreover, it is essential to assess the various features of the data quantitatively so that relationships in anatomical and functional domains between complementing modalities can be expressed mathematically. This paper presents a clinically feasible software environment for the quantitative assessment of the relationship among biochemical functions as assessed by PET imaging and electrophysiological parameters derived from intracranial EEG. Based on the developed software tools, quantitative results obtained from individual modalities can be merged into a data structure allowing a consistent framework for advanced data mining techniques and 3D visualization. Moreover, an effort was made to derive quantitative variables (such as the spatial proximity index, SPI) characterizing the relationship between complementing modalities on a more generic level as a prerequisite for efficient data mining strategies. We describe the implementation of this software environment in twelve children (mean age 5.2 ± 4.3 years) with medically intractable partial epilepsy who underwent both high-resolution structural MR and functional PET imaging. Our experiments demonstrate that our approach will lead to a better understanding of the mechanisms of epileptogenesis and might ultimately have an impact on treatment. Moreover, our software environment holds promise to be useful in many other neurological disorders, where integration of multimodality data is crucial for a better understanding of the underlying disease mechanisms

A Systematic Review of Reported Cost for Smear and Culture Tests during Multidrug-Resistant Tuberculosis Treatment

Background: In 2011, World Health Organization revised its recommendation for microbiological monitoring during treatment for multidrug-resistant tuberculosis (MDR-TB) by increasing the frequency of culture examination from quarterly to monthly after culture conversion. Implementing the recommendation requires substantial additional investment in laboratory infrastructure. The objective of this review is to provide cost evidence that is needed for national TB programs to budget for optimal monitoring strategies. Methods and Findings: We conducted the first systematic literature review on unit cost estimates of three monitoring strategies: 1) smear only; 2) culture only; 3) combined smear and culture. 26 peer-reviewed studies were selected by searching 10 databases in English and Chinese for literature published between 1995 and 2012. Cost estimates were converted into 2010 constant USD and international dollars. We assessed the quality of the estimates using a matrix with five essential elements and provided a cost projection for the combined smear and culture tests where the data were available. The 26 studies reported the cost estimates in 16 predominantly high- or middle-income countries from 1993 to 2009. The estimated unit cost for smear, culture, and combined tests ranges from $0.26 to$10.50, $1.63 to$62.01, and $26.73 to$39.57, respectively. The ratio of culture to smear costs varies from 1.35 to 11.98. The wide range of estimates is likely attributable to using different laboratory methods in different regions and years and differing practices in collecting and reporting cost data. Most studies did not report information critical for generalizing their conclusions. Conclusion: The paucity and low quality of unit cost estimates for TB monitoring in resource-poor settings impose technical challenges in predicting the resources needed for strengthening microbiological monitoring. To improve the validity and comparability of the cost data, we strongly advocate the data collection, estimation, and reporting follow protocols proposed by WHO

The influence of longitudinal mentoring on medical student selection of primary care residencies

Background The number of students selecting careers in primary care has declined by 41% in the last decade, resulting in anticipated shortages. Methods First-year medical students interested in primary care were paired with primary care mentors. Mentors were trained, and mentors and students participated in focus groups at the end of each academic year. Quantitative and qualitative results are presented. Results Students who remained in the mentoring program matched to primary care programs at 87.5% in the first year and 78.9% in the second year, compared to overall discipline-specific match rates of 55.8% and 35.9% respectively. Students reported a better understanding of primary care and appreciated a relationship with a mentor. Conclusions A longitudinal mentoring program can effectively support student interest in primary care if it focuses on the needs of the students and is supportive of the mentors

Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer.

The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent

Coordinated prophylactic surgical management for women with hereditary breast-ovarian cancer syndrome

<p>Abstract</p> <p>Background</p> <p>Women with <it>BRCA1 </it>or <it>BRCA2 </it>mutations have a substantially increased risk of breast and ovarian cancer compared with the general population. Therefore, prophylactic mastectomy (PM) and bilateral salpingo-oophorectomy (BSO) have been proposed as risk-reduction strategies for <it>BRCA1/2 </it>mutation carriers. We aimed to assess the feasibility of coordinated PM and BSO in hereditary breast-ovarian cancer syndrome.</p> <p>Methods</p> <p>High risk women for breast and ovarian cancer who underwent coordinated PM and BSO were included in this study. Clinical characteristics and surgical and oncologic outcomes were retrospectively reviewed.</p> <p>Results</p> <p>Twelve patients underwent coordinated PM and BSO. Ten had history of previous breast cancer. Autologous breast reconstruction was performed in ten patients. The mean age at surgery was 43 (range 34–65). Mean operating time was 9.3 hours (range 3–16) with a mean postoperative hospitalization of 5.4 days (range 4–8). Intraoperatively, there were no major surgical complications. Postoperatively, one patient developed an abdominal wound dehiscence, another reoperation for flap congestion; one had umbilical superficial epidermolysis, and one patient developed aspiration pneumonia. At a mean follow-up of 84 months, 10 of patients were cancer-free. Although no patients developed a new primary cancer, two developed a distant recurrence.</p> <p>Conclusion</p> <p>Coordinated PM and BSO is a feasible procedure with acceptable morbidity in selected high-risk patients that desire to undergo surgery at one operative setting.</p

Prostate cancer theranostics - An overview

Metastatic prostate cancer is incurable, and novel methods to detect the disease earlier and to direct definitive treatment are needed. Molecularly specific tools to localize diagnostic and cytotoxic radionuclide payloads to cancer cells and the surrounding microenvironment are recognized as a critical component of new approaches to combat this disease. The implementation of theranostic approaches to characterize and personalize patient management is beginning to be realized for prostate cancer patients. This review article summarized clinically translated approaches to detect, characterize, and treat disease in this rapidly expanding field

Interactions of partial LSD analogs with behavioral disrupting effects of LSD and DMT in the rat

Adult male Holtzman rats were trained to barpress on a schedule whereby every fourth press earned a reward of 0.01 ml of sugar-sweetened milk (FR4). After an i.p. injecton of LSD (0.1 mg/kg) or DMT (3.2 or 10 mg/kg) such barpressing is abolished completely and resumed, usually within an hour, at a rate near the preinjection control rate of pressing. It continues at a steady, uninterrupted pace until animals are removed from the operant chamber one-half hour later. A series of N,N-diethylnipecotamide derivatives were synthesized and tested for their ability to modify the disruptive effect of these hallucinogens. N,N-diethylbutyramide (DBA) and 1-methyl-1,2,5,6-tetrahydropyridine-3-(N,N-diethylcarboxamide) (THPC) were also tested. Pretreatment with a single i.p. injection of any of these compounds (5-40 mg/kg) either had no effect on or else prolonged the duration of hallucinogen-induced cessation of barpressing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22701/1/0000255.pd

REST and Its Corepressors Mediate Plasticity of Neuronal Gene Chromatin throughout Neurogenesis

SummaryRegulation of neuronal gene expression is critical to central nervous system development. Here, we show that REST regulates the transitions from pluripotent to neural stem/progenitor cell and from progenitor to mature neuron. In the transition to progenitor cell, REST is degraded to levels just sufficient to maintain neuronal gene chromatin in an inactive state that is nonetheless poised for expression. As progenitors differentiate into neurons, REST and its corepressors dissociate from the RE1 site, triggering activation of neuronal genes. In some genes, the level of expression is adjusted further in neurons by CoREST/MeCP2 repressor complexes that remain bound to a site of methylated DNA distinct from the RE1 site. Expression profiling based on this mechanism indicates that REST defines a gene set subject to plasticity in mature neurons. Thus, a multistage repressor mechanism controls the orderly expression of genes during development while still permitting fine tuning in response to specific stimuli